European Journal of Vascular & Endovascular Surgery
Volume 31, Issue 1 , Pages 59-63, January 2006

Association of Cardiovascular Risk Factors with Pattern of Lower Limb Atherosclerosis in 2659 Patients Undergoing Angioplasty

  • N. Diehm

      Affiliations

    • Division of Angiology, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, Bern, Switzerland
    • ,
  • A. Shang

      Affiliations

    • Department of Social and Preventive Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland
    • ,
  • A. Silvestro

      Affiliations

    • Division of Angiology, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, Bern, Switzerland
    • ,
  • D.-D. Do

      Affiliations

    • Division of Angiology, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, Bern, Switzerland
    • ,
  • F. Dick

      Affiliations

    • Department of Cardiovascular Surgery, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, Bern, Switzerland
    • ,
  • J. Schmidli

      Affiliations

    • Department of Cardiovascular Surgery, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, Bern, Switzerland
    • ,
  • F. Mahler

      Affiliations

    • Division of Angiology, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, Bern, Switzerland
    • ,
  • I. Baumgartner

      Affiliations

    • Division of Angiology, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, Bern, Switzerland
    • Corresponding Author InformationCorresponding author. Iris Baumgartner, MD, Division of Angiology, Swiss Cardiovascular Center, University Hospital, Freiburgstrasse, 3010 Bern, Switzerland.

Accepted 28 September 2005. published online 08 November 2005.

Article Outline

Abstract 

Objectives

Aim of this study is to correlate distribution pattern of lower limb atherosclerosis with cardiovascular risk factor profile of patients with peripheral arterial occlusive disease (PAD).

Patients and methods

Analysis is based on a consecutive series of 2659 patients (1583 men, 1076 women, 70±11 years) with chronic PAD of atherosclerotic origin undergoing primary endovascular treatment of lower extremity arteries. Pattern of atherosclerosis was grouped into iliac (n=1166), femoropopliteal (n=2151) and infrageniculate (n=888) disease defined according to target lesions treated. A multivariable multinomial logistic regression analysis was performed to assess relation with age, gender and classical cardiovascular risk factors (diabetes mellitus, arterial hypertension, hypercholesterolemia, cigarette smoking) using femoropopliteal disease as reference.

Results

Iliac disease was associated with younger age (RRR 0.95 per year of age, 95%-CI 0.94–0.96, p<0.001), male gender (RRR 1.32, 95%-CI 1.09–1.59, p=0.004) and cigarette smoking (RRR 2.02, 95%-CI 1.68–2.42, p<0.001). Infrageniculate disease was associated with higher age (RRR 1.02, 95%-CI 1.01–1.02, p<0.001), male gender (RRR 1.23, 95%-CI 1.06–1.41, p=0.005) and diabetes mellitus (RRR 1.68, 95%-CI 1.47–1.92, p<0.001). Hypercholesterolemia was less prevalent in patients with lesions below the knee (RRR 0.82, 95%-CI 0.71–0.94, p=0.006), whereas no distinct pattern was apparent related to arterial hypertension.

Conclusion

Clinical phenotype of peripheral atherosclerosis varies with prevalence of cardiovascular risk factors suggesting differences in mechanisms involved in iliac as compared with infrageniculate lesions. Identification of molecular mechanism might have influence on future therapeutic strategies in PAD patients.

Keywords: Age, Cohort study, Diabetes mellitus, Gender, Hypercholesterolemia, Hypertension, Smoking

 

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1. Introduction 

Atherosclerosis is the leading cause of death in western countries and represents one of the major problems in vascular medicine.1, 2, 3 The systemic nature of atherosclerotic disease is clearly evident from the frequent concurrence of coronary, cerebrovascular and peripheral arterial disease (PAD),4, 5, 6 with plaque rupture leading to atherothrombosis.

Large epidemiological and autopsy-based studies have shown that distribution, extent and progression of atherosclerosis are influenced by cardiovascular risk factors,4, 5, 7, 8, 9, 10, 11, 12, 13 but not in an uniform pattern. Cigarette smoking and hypercholesterolemia are most important in coronary artery disease,9, 13 arterial hypertension and diabetes mellitus are more frequent among patients with cerebrovascular disease.10, 14 Lower extremity atherosclerosis is considered to be strongly related to smoking and diabetes mellitus.4, 7, 9, 15 However, there are striking dissimilarities between arterial regions of the lower extremities16, 17, 18, 19, 20, 21 with the predominant below knee involvement in diabetic patients most obvious.17

The aim of this cohort study of patients undergoing primary endovascular treatment of lower limb arteries is to analyse risk factor association with distribution pattern of peripheral atherosclerotic target lesions.

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2. Patients and Methods 

The cohort originates from a consecutive registry of patients with endovascular therapy in a tertiary referral center responsible for peripheral vascular service in a population of about one million subjects. Between January 1996 and June 2003, 2659 patients (1076 women, mean age 70±11 years) with primary angioplasty (±stenting) of lower extremity arteries were enrolled (3346 limbs, 4205 target lesions).

All patients had chronic PAD of Fontaine stages II–IV of atherosclerotic origin. Patients with acute limb ischemia, non-atherosclerotic lesions and redo interventions were excluded from analysis.

Prior to endovascular revascularization, all patients had undergone clinical workup and arterial duplex ultrasound to confirm findings suspected by clinical examination.

Target lesions treated defined relevant atherosclerotic disease manifestation. Location of target lesions was grouped as iliac or proximal (common, external and internal iliac artery), femoropopliteal (common, superficial and deep femoral arteries, popliteal artery) and infrageniculate or distal (tibiofibular trunk, anterior and posterior tibial arteries, fibular artery) disease. Risk factors included in the statistical model were age, gender, diabetes mellitus, arterial hypertension, hypercholesterolemia and cigarette smoking. The presence of diabetes mellitus was defined by fasting blood sugar >120mg/dL or glycosylated haemoglobin >6% or if the patient was on hypoglycemic drugs. The presence of arterial hypertension was defined by systolic blood pressure >140mmHg and/or diastolic blood pressure >80mmHg, or if the patient consumed any antihypertensive drug. The presence of hyperlipidemia was defined by total cholesterol level >5mmol/L, or high-density lipoprotein (HDL) cholesterol <1mmol/L, or triglycerides >2mmol/L, or if the patient consumed any lipid-lowering drug. Furthermore, patients were classified as smokers and non-smokers. A smoking history (current or former smokers) was established in patients who had 1 pack-year or more of tobacco use based on patient interview or chart documentation.

2.1. Statistics 

The Department of Social and Preventive Medicine, University of Bern performed statistical analysis. Descriptive analyses of socio-demographic characteristics were based on patient characteristics at the time of the first intervention. Demographic and clinical characteristics of study population are reported as mean±SD for continuous variables and as number (percentage) for categorical variables. Each target lesion was counted once and classified according to its location (iliac, femoropopliteal, infragenigular). We used multivariable multinomial logistic regression to analyse risk factor associations at the level of lesions. Femoropopliteal lesions were defined as reference category. Since, some patients had more than one target lesion, robust standard errors were used to allow for the multilevel nature of the data. Results are shown as relative risk ratio (RRR) with 95% confidence intervals (95%-CI). A p<0.05 was considered statistically significant. All analyses were performed in Stata version 8.2 (Stata Corporation, College Station, Texas).

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3. Results 

Demographic data among the 2659 patients treated are shown in Table 1. Location of the 4205 atherosclerotic target lesions in 3346 limbs treated was in the iliac territory in 27.7% (1166 lesions/883 patients), femoropopliteal 51.2% (2151 lesions/1802 patients) and infragenicular 21.1% (888 lesions/801 patients), respectively.

Table 1. Demographic data of 2659 patients included in the cohort
Patient characteristics
Male, n1583 (59.5%)
Age (mean±SD), years70±11
Diabetes mellitus, n891 (33.5%)
Hypertension, n1497 (56.3%)
Hypercholesterinemia, n1215 (45.7%)
Current smoking, n1144 (43.0%)

Results from multivariable multinomial logistic regression analysis showing the association between atherosclerotic target lesions (iliac, femoropoliteal, infragenicular) with risk factors are given in Table 2 and Fig. 1. Statistically, femoropopliteal involvement was set with a RRR of 1. Risk for atherosclerotic disease increased with age, giving a RRR of 0.95 (95%-CI 0.94–0.96, p<0.001) for iliac, and a RRR of 1.02 (95%-CI 1.01–1.02, p<0.001) for infragenicular lesions calculated per year of age. A more pronounced centrifugal pattern was seen in patients with diabetes mellitus (RRR 0.59, 95%-CI 0.49–0.72, p<0.001 for iliac, and RRR 1.68, 95%-CI 1.47–1.92, p<0.001 for infragenicular lesions, respectively), whereas cigarette smoking demonstrated the inverse association (RRR 2.02, 95%-CI 1.68–2.42, p<0.001 for iliac, and RRR 0.50, 95%-CI 0.42–0.59, p<0.001 for infragenicular lesions, respectively). Hypercholesterolemia showed a similar pattern as seen related to smoking, but missed statistical significance for iliac disease involvement. Gender was associated with femoropopliteal lesions in females, in contrast to iliac (RRR 1.32, 95%-CI 1.09–1.59 p=0.004) and infragenicular (RRR 1.23, 95%-CI 1.06–1.41, p=0.005) manifestation of target lesions in males. Arterial hypertension had no significant discriminating effect for a distinct pattern of atherosclerosis (Table 2).

Table 2. Multivariable multinominal logistic regression analysis to calculate risk factor associations at the level of atherosclerotic target lesions (n=4205)
Risk factorAtherosclerotic lesions
IliacFemoropopliteal (reference)Infragenicular
RRR95%-CIRRRRRR95%-CI
Age (per year)0.950.94–0.9611.021.01–1.02
Male gender1.321.09–1.5911.231.06–1.41
Diabetes mellitus0.590.49–0.7211.681.47–1.92
Hypertension1.170.99–1.3911.060.92–1.22
Hypercholesterolemia1.150.98–1.3610.820.71–0.94
Current smoking2.021.68–2.4210.500.42–0.59

Femoropopliteal lesions were used as reference with a relative risk ratio (RRR) of 1.

  • View full-size image.
  • Fig. 1. 

    Association of risk factors with the level of atherosclerotic target lesions. Red overlay on the anatomic cartoon illustrates the association of risk factor with pattern of atherosclerotic lesions.

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4. Discussion 

This cohort study of patients with chronic PAD undergoing primary endovascular treatment highlights a statistically significant association between cardiovascular risk factors present and pattern of atherosclerotic lesions of the lower limbs. Current smoking is closely related to proximal disease, whereas higher age and diabetes mellitus predispose to distal atherosclerotic disease involvement. Moreover, a striking difference with more femoropopliteal target lesions in females compared with significantly more iliac and infragenicular target lesions in males is evident.

Hypotheses explaining site-selectivity of atherosclerotic lesions include hemodynamic stress related to arterial geometry and anatomic, cellular or biochemical variations in the arterial wall.22 Iliac arteries are characterized by elastic properties, whereas femoral and infragenicular arteries contain progressively more muscular elements. Moreover, the relation of arterial lumen to wall thickness decreases from proximal to distal, both generating an alteration in arterial flow and shear stress associated with endothelial dysfunction and early type I–III atherosclerotic lesions at sites with low shear rate and disturbed flow.

Age-related effects on site-selectivity of atherosclerotic lesions within the peripheral circulation were observed in several small sized angiographic studies.19, 20, 21, 23, 24 In the presented study, patients with iliac obstructions are shown to be substantially younger, whereas older patients are more susceptible to the development of lesions in femoropopliteal and infrageniculate arteries, suggesting that mechanisms of premature atherosclerosis in peripheral arteries are different from the senescent form.

Significantly, more men were treated in this study reflecting observations from other studies that evolution of PAD is strongly influenced by gender, with male dominance.13, 25, 26, 27, 28, 29 Moreover, atherosclerosis pattern significantly differed between male and female patients, as is known from clinical practice. In contrary to the strong association of iliac disease with male gender, a pattern of isolated manifestation of atherosclerosis in the aorto-iliac segment (Brewster type I disease) has been described in younger females.23, 24, 30 Differences from the present observation are explained by the fact that for statistical reasons aortic target lesions were not considered. A similar striking female dominance for isolated aorto-iliac lesions was seen in patients from the registry if these lesions were included (data not shown).

Diabetes mellitus is the most obvious risk factor for atherosclerotic involvement of infragenicular arteries. This fact has first been mentioned by Strandness in 1964, and has been confirmed by several authors including this series.19, 21, 31, 32, 33, 34, 35, 36

The following limitations of the present cohort study have to be addressed. Atherosclerotic pattern was defined by endovascular target lesions treated. Consequently, the entire atherosclerotic burden was not considered for analysis. However, PTA target lesions represent clinically relevant atherosclerosis, although it does not contain information about early atherosclerotic lesions.

We are aware that grouping the treated vessels into three categories might be an over-simplification. We do not think that a more differentiated analysis of vascular territories would have changed our basic message. Furthermore, we cannot rule out a bias created by only including patients selected for endovascular therapy.

In conclusion, our results show significant variation in site-selectivity of atherosclerotic lesions related to cardiovascular risk factor profile present. The findings suggest profound differences in molecular mechanisms involved. The use of gene profiling and novel imaging approaches will help to unravel complex interactions.

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PII: S1078-5884(05)00592-7

doi:10.1016/j.ejvs.2005.09.006

European Journal of Vascular & Endovascular Surgery
Volume 31, Issue 1 , Pages 59-63, January 2006

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